Review of alpha-gal syndrome highlights tick bite link and knowledge gapsTick bites may explain why some people develop alpha-gal allergy

The α-Gal syndrome (AGS) is an emerging form of food allergy characterized by delayed hypersensitivity reactions to mammalian meat products and mediated by IgE antibodies specific to the carbohydrate galactose-α-1,3-galactose (α-Gal). Although α-Gal–specific IgG, IgM and IgA antibodies are generally present in humans as a consequence of continuous exposure to commensal microbiota and dietary sources, IgE sensitization to α-Gal occurs only in a subset of individuals. Epidemiological and experimental evidence has firmly linked this sensitization to tick bites. Multiple ticks across continents have been implicated in α-Gal sensitization, and α-Gal has been detected in tick midgut, hemolymph, and salivary glands; yet the precise origin of α-Gal within ticks and the immunological mechanisms that drive α-Gal-specific IgE production remain incompletely understood. In particular, it remains unclear how cutaneous exposure to ticks promotes IgE class switching against α-Gal, whereas lifelong gastrointestinal exposure to the same epitope does not elicit allergic sensitization. Despite a growing number of reviews addressing the clinical and epidemiological aspects of AGS, significant gaps persist in our understanding of the molecular and immunological pathways underlying disease development. This review aims to address these gaps by focusing specifically on the molecular and immunological pathways involved in α-Gal sensitization following tick bites, with particular emphasis on the innate and adaptive immune responses that drive the production of α-Gal-specific IgE. By integrating data from human studies, animal models and in vitro systems, a more cohesive understanding of the immune dynamics contributing to Th2-biased immune responses and sensitization begins to emerge. Ultimately, a detailed understanding of how the cutaneous environment, tick saliva components, and host factors synergize to induce a Th2-biased IgE sensitization is key to identifying diagnostic biomarkers and prevention approaches.